Abstract: Details of interactions between commensal bacteria and the human intestinal epithelia are increasingly being resolved at the molecular level. Gut microorganisms play key supporting roles in digestion, immunity, and enteric homeostasis, but their exchanges with intestinal epithelia cells (IECs) are at once symbiotic and confrontational. This environment of interspecies cross- communication has tremendous potential for therapeutic applications. If commensal bacteria can be engineered to mediate or inhibit specific signaling cascades, they could be used as in vivo "relay stations": accessing the bloodstream, and thereby the entire host with highly specific signaling targets. The proposed work will examine the use of commensal bacteria for the controlled expression of an insulin-stimulating peptide GLP-1 into the intestinal epithelial cell space. The use of commensal strains for controlled release of GLP-1 into or near the mucosal lining of the gut may mediate a surrogate glucose regulatory mechanism. We have already shown this to be the case in mouse models of diabetes. The result, if translated to humans would be an orally-dosed treatment for type-1 diabetes that would potentially mediate the long term effects of diabetes and allow the patient to live normoglycemically for only pennies per day. Further, this research will develop a 3D culture model of the small intestinal villi. The model will differentiate intestinal stem cells into the four types of enterocyte within a 3D physiologically-relevant space. It will provide research in this area a much needed high throughput tool. Public Health Relevance: This work will provide a potential treatment for type-1 diabetes that will eliminate the need for insulin injection and potentially eliminate the long-term complications associated with this disease. The treatment would cost only pennies per day.